Pyrimidine derivatives as gpcr modulators for use in the treatment of obesity and diabetes

ABSTRACT

The present invention relates to Pyriraidine Derivatives of formula (I), compositions comprising a Pyrimidine Derivative, and methods of using the Pyrimidine Derivatives for treating or preventing obesity, diabetes, a diabetic complication, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of a G protein-coupled receptor (GPCR) in a patient.

FIELD OF THE INVENTION

The present invention relates to Pyrimidine Derivatives, compositionscomprising a Pyrimidine Derivative, and methods of using the PyrimidineDerivatives for treating or preventing obesity, diabetes, a diabeticcomplication, a metabolic disorder, a cardiovascular disease or adisorder related to the activity of a G protein-coupled receptor (GPCR)in a patient.

BACKGROUND OF THE INVENTION

Although a number of receptor classes exist in humans, by far the mostabundant and therapeutically relevant is represented by the GPCR class.It is estimated that there are some 100,000 genes within the humangenome, and of these, approximately 2% or 2,000 genes, are estimated tocode for GPCRs. Receptors, including GPCRs, for which the endogenousligand has been identified are referred to as “known” receptors, whilereceptors for which the endogenous ligand has not been identified arereferred to as “orphan” receptors. GPCRs represent an important area forthe development of pharmaceutical products, as evidenced by the factthat pharmaceutical products have been developed from approximately 20of the 100 known GPCRs. This distinction is not merely semantic,particularly in the case of GPCRs.

GPCRs share a common structural motif. All these receptors have sevensequences of between 22 to 24 hydrophobic amino acids that form sevenalpha helices, each of which spans the membrane (each span is identifiedby number, i.e., transmembrane-1 (TM-1), transmembrane-2 (TM-2), etc.).The transmembrane helices are joined by strands of amino acids betweentransmembrane-2 and transmembrane-3, transmembrane-4 andtransmembrane-5, and transmembrane-6 and transmembrane-7 on theexterior, or “extracellular” side, of the cell membrane (these arereferred to as “extracellular” regions 1, 2 and 3 (EC-1, EC-2 and EC-3),respectively). The transmembrane helices are also joined by strands ofamino acids between transmembrane-1 and transmembrane-2, transmembrane-3and transmembrane-4, and transmembrane-5 and transmembrane-6 on theinterior, or “intracellular” side, of the cell membrane (these arereferred to as “intracellular” regions 1, 2 and 3 (IC-1, IC-2 and IC-3),respectively). The “carboxy” (“C”) terminus of the receptor lies in theintracellular space within the cell, and the “amino” (“N”) terminus ofthe receptor lies in the extracellular space outside of the cell.

Generally, when an endogenous ligand binds with the receptor (oftenreferred to as “activation” of the receptor), there is a change in theconformation of the intracellular region that allows for couplingbetween the intracellular region and an intracellular “G-protein.” Ithas been reported that GPCRs are “promiscuous” with respect to Gproteins, i.e., that a GPCR can interact with more than one G protein.See, Kenakin, T., Life Sciences 43, 1095 (1988). Although other Gproteins exist, currently, Gq, Gs, Gi, and Go are G proteins that havebeen identified. Endogenous ligand-activated GPCR coupling with theG-protein begins a signaling cascade process (referred to as “signaltransduction”). Under normal conditions, signal transduction ultimatelyresults in cellular activation or cellular inhibition. It is thoughtthat the IC-3 loop as well as the carboxy terminus of the receptorinteract with the G protein.

Under physiological conditions, GPCRs exist in the cell membrane inequilibrium between two different conformations: an “inactive” state andan “active” state. A receptor in an inactive state is unable to link tothe intracellular signaling transduction pathway to produce a biologicalresponse. Changing the receptor conformation to the active state allowslinkage to the transduction pathway (via the G-protein) and produces abiological response. A receptor can be stabilized in an active state byan endogenous ligand or a compound such as a drug.

Modulation of G-protein coupled receptors has been well-studied forcontrolling various metabolic disorders. Small molecule modulators ofthe receptor GPR119, a G-protein coupled-receptor described in, forexample, GenBank (see, e.g., accession numbers XM.sub.—066873 andAY288416), have been shown to be useful for treating or preventingcertain metabolic disorders. GPR119 is a G protein-coupled receptor thatis selectively expressed on pancreatic beta cells. GPR119 activationleads to elevation of a level of intracellular cAMP, consistent withGPR119 being coupled to Gs. Agonists to GPR119 stimulateglucose-dependent insulin secretion in vitro and lower an elevated bloodglucose level in vivo. See, e.g., International Publication Nos. WO04/065380 and WO 04/076413, and European Patent Application No. EP1338651, the disclosure of each of which is herein incorporated byreference in its entirety.

U.S. Pat. No. 7,136,426 discloses pyrazolo[3,4-d]pyrimidine ethers andrelated compounds as modulators of the GPR119 receptor that are usefulfor the treatment of various metabolic-related disorders such as type Idiabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. The compounds are alsoreported as being useful for controlling weight gain, controlling foodintake, and inducing satiety in mammals. The promising nature of theseGPCR modulators indicates a need in the art for additional smallmolecule GPCR modulators with improved efficacy and safety profiles.This invention addresses that need.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, esters and prodrugsthereof, wherein:

R¹ is H, alkyl, halo or —O-alkyl;

R^(2a) is H or alkyl, or R^(2a) and R^(2b) join to form —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂OCH₂—;

R^(2b) is H or alkyl;

R^(3a) is H or alkyl, or R^(3a) and R^(3b) join to form —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂OCH₂—;

R^(3b) is H or alkyl;

R⁴ is alkyl, cycloalkyl, haloalkyl, aryl, -alkylene-aryl or heteroaryl,wherein an aryl or heteroaryl group can be optionally substituted withone or more groups, which can be the same or different, and are selectedfrom alkyl, halo, haloalkyl, —O-alkyl, —CN and —S(O)₂-alkyl;

R⁵ is alkyl, cycloalkyl, haloalkyl, -alkylene-aryl, alkenyl or—N(alkyl)₂;

R⁶ is H or alkyl;

A is a bond when Q is —N—, and A is —N(R⁶)— when Q is —CH—;

Q is —N— or —CH—;

W is —C(O)—, —C(O)O—, or —S(O)₂—;

Y is —O—, —S—, —NH— or —CH₂— when Z is —CH—, and Y is a bond when Z is—N—;

Z is —CH— or —N—;

each occurrence of n is independently 0, 1 or 2; and

each occurrence of p is 0, 1 or 2, such that when Q and Z are both —N—,then each occurrence of p is 1 or 2.

The compounds of formula (I) and pharmaceutically acceptable salts,solvates, esters or prodrugs thereof (referred to collectively herein asthe “Pyrimidine Derivatives”) can be useful for treating or preventingobesity, diabetes, a diabetic complication, metabolic syndrome, acardiovascular disease or a disorder related to the activity of a GPCR(each being a “Condition”) in a patient.

Also provided by the invention are methods for treating or preventing aCondition in a patient, comprising administering to the patient aneffective amount of one or more Pyrimidine Derivatives.

The present invention further provides compositions comprising aneffective amount of one or more Pyrimidine Derivatives or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof, and a pharmaceutically acceptable carrier. Thecompositions can be useful for treating or preventing a Condition in apatient.

The details of the invention are set forth in the accompanying detaileddescription below.

Although any methods and materials similar to those described herein canbe used in the practice or testing of the present invention,illustrative methods and materials are now described. Other features,objects, and advantages of the invention will be apparent from thedescription and the claims. All patents and publications cited in thisspecification are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides Pyrimidine Derivativesof Formula (I), compositions comprising one or more PyrimidineDerivatives, and methods of using the Pyrimidine Derivatives fortreating or preventing a Condition in a patient.

Definitions and Abbreviations

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a non-human mammal,including, but not limited to, a monkey, dog, baboon, rhesus, mouse,rat, horse, cat or rabbit. In another embodiment, a patient is acompanion animal, including but not limited to a dog, cat, rabbit, horseor ferret. In one embodiment, a patient is a dog. In another embodiment,a patient is a cat.

The term “obesity” as used herein, refers to a patient being overweightand having a body mass index (BMI) of 25 or greater. In one embodiment,an obese patient has a BMI of 25 or greater. In another embodiment, anobese patient has a BMI from 25 to 30, in another embodiment, an obesepatient has a BMI greater than 30. In still another embodiment, an obesepatient has a BMI greater than 40.

The term “obesity-related disorder” as used herein refers to: (i)disorders which result from a patient having a BMI of 25 or greater; and(ii) eating disorders and other disorders associated with excessive foodintake. Non-limiting examples of an obesity-related disorder includeedema, shortness of breath, sleep apnea, skin disorders and high bloodpressure.

The term “metabolic syndrome” as used herein, refers to a set of riskfactors that make a patient more susceptible to cardiovascular diseaseand/or type 2 diabetes. A patient is said to have metabolic syndrome ifthe patient simultaneously has three or more of the following five riskfactors:

-   -   1) central/abdominal obesity as measured by a waist        circumference of greater than 40 inches in a male and greater        than 35 inches in a female;    -   2) a fasting triglyceride level of greater than or equal to 150        mg/dL;    -   3) an HDL cholesterol level in a male of less than 40 mg/dL or        in a female of less than 50 mg/dL;    -   4) blood pressure greater than or equal to 130/85 mm Hg; and    -   5) a fasting glucose level of greater than or equal to 110        mg/dL.

The term “effective amount” as used herein, refers to an amount ofPyrimidine Derivative and/or an additional therapeutic agent, or acomposition thereof that is effective in producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect whenadministered to a patient suffering from a Condition. In the combinationtherapies of the present invention, an effective amount can refer toeach individual agent or to the combination as a whole, wherein theamounts of all agents administered are together effective, but whereinthe component agent of the combination may not be present individuallyin an effective amount.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup which may be straight or branched and which contains from about 1to about 20 carbon atoms. In one embodiment, an alkyl group containsfrom about 1 to about 12 carbon atoms. In another embodiment, an alkylgroup contains from about 1 to about 6 carbon atoms. Non-limitingexamples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl,isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl group may beunsubstituted or substituted by one or more substituents which may bethe same or different, each substituent being independently selectedfrom the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl,cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂,—NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, analkyl group is unsubstituted. In another embodiment, an alkyl group islinear. In another embodiment, an alkyl group is branched.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched and contains from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkenyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groupsinclude ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl,octenyl and decenyl. An alkenyl group may be unsubstituted orsubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy,—O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, analkenyl group is unsubstituted.

The term “alkynyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and which may bestraight or branched and contains from about 2 to about 15 carbon atoms.In one embodiment, an alkynyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkynyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynylgroup may be unsubstituted or substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkenyl, alkynyl, aryl,cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl,alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In oneembodiment, an alkynyl group is unsubstituted.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 toabout 6 carbon atoms. In another embodiment, an alkylene group isbranched. In another embodiment, an alkylene group is linear.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to about10 carbon atoms. An aryl group can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein below. In one embodiment, an aryl group can beoptionally fused to a cycloalkyl or oxocycloalkyl group. Non-limitingexamples of aryl groups include phenyl and naphthyl. In one embodiment,an aryl group is unsubstituted. In another embodiment, an aryl group isphenyl.

The term “cycloalkyl,” as used herein, refers to a non-aromatic mono- ormulticyclic ring system comprising from about 3 to about 10 ring carbonatoms. In one embodiment, a cycloalkyl contains from about 5 to about 10ring carbon atoms. In another embodiment, a cycloalkyl contains fromabout 5 to about 7 ring atoms. The term “cycloalkyl” also encompasses acycloalkyl group, as defined above, that is fused to an aryl (e.g.,benzene) or heteroaryl ring. Non-limiting examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. Non-limiting examples of multicycliccycloalkyls include 1-decalinyl, norbornyl and adamantyl. A cycloalkylgroup can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. In one embodiment, a cycloalkyl group is unsubstituted. Aring carbon atom of a cycloalkyl group may be functionalized as acarbonyl group. An illustrative example of such a cycloalkyl group isoxocyclopentyl:

The term “cycloalkenyl,” as used herein, refers to a non-aromatic mono-or multicyclic ring system comprising from about 3 to about 10 ringcarbon atoms and containing at least one endocyclic double bond. In oneembodiment, a cycloalkenyl contains from about 5 to about 10 ring carbonatoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl,cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A cycloalkenyl groupcan be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedherein below. In one embodiment, a cycloalkenyl group is unsubstituted.In another embodiment, a cycloalkenyl group is a 5-memberedcycloalkenyl.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 4 of the ring atoms is independently O, N or S and theremaining ring atoms are carbon atoms. In one embodiment, a heteroarylgroup has 5 to 10 ring atoms. In another embodiment, a heteroaryl groupis monocyclic and has 5 or 6 ring atoms. A heteroaryl group can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein below. Aheteroaryl group is joined via a ring carbon atom, and any nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.The term “heteroaryl” also encompasses a heteroaryl group, as definedabove, that is fused to a benzene ring, Non-limiting examples ofheteroaryls include pyridyl, pyrazinyl, (uranyl, thienyl, pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and thelike. The term “heteroaryl” also refers to partially saturatedheteroaryl moieties such as, for example, tetrahydroisoquinolyl,tetrahydroquinolyl and the like. In one embodiment, a heteroaryl groupis unsubstituted. In another embodiment, a heteroaryl group is a5-membered heteroaryl. In another embodiment, a heteroaryl group is a6-membered heteroaryl.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to about 10ring atoms, wherein from 1 to 4 of the ring atoms are independently O, Sor N and the remainder of the ring atoms are carbon atoms. Aheterocycloalkyl group can be joined via a ring carbon or a ringnitrogen atom. In one embodiment, a heterocycloalkyl group has fromabout 5 to about 10 ring atoms. In another embodiment, aheterocycloalkyl group has 5 or 6 ring atoms. There are no adjacentoxygen and/or sulfur atoms present in the ring system. Any —NH group ina heterocycloalkyl ring may exist protected such as, for example, as an—N(BOC), —N(Cbz), —N(Tos) group and the like; such protectedheterocycloalkyl groups are considered part of this invention. The term“heterocycloalkyl” also encompasses a heterocycloalkyl group, as definedabove, that is fused to an aryl (e.g., benzene) or heteroaryl ring. Aheterocycloalkyl group can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein below. The nitrogen or sulfur atom of theheterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclicheterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.A ring carbon atom of a heterocycloalkyl group may be functionalized asa carbonyl group. An illustrative example of such a heterocycloalkylgroup is pyrrolidonyl:

In one embodiment, a heterocycloalkyl group is unsubstituted. In anotherembodiment, a heterocycloalkyl group is a 5-membered heterocycloalkyl.In another embodiment, a heterocycloalkyl group is a 6-memberedheterocycloalkyl.

The term “heterocycloalkenyl,” as used herein, refers to aheterocycloalkyl group, as defined above, wherein the heterocycloalkylgroup contains from 3 to 10 ring atoms, and at least one endocycliccarbon-carbon or carbon-nitrogen double bond. In one embodiment, aheterocycloalkenyl group has from 5 to 10 ring atoms. In anotherembodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ringatoms. A heterocycloalkenyl group can optionally substituted by one ormore ring system substituents, wherein “ring system substituent” is asdefined above. The nitrogen or sulfur atom of the heterocycloalkenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of heterocycloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, andthe like. A ring carbon atom of a heterocycloalkenyl group may befunctionalized as a carbonyl group. Illustrative examples of suchheterocycloalkenyl groups include, but are not limited to:

In one embodiment, a heterocycloalkenyl group is unsubstituted. Inanother embodiment, a heterocycloalkenyl group is a 5-memberedheterocycloalkenyl. In another embodiment, a heterocycloalkenyl group isa 6-membered heterocycloalkenyl.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

The term “ring system substituent,” as used herein, refers to asubstituent group attached to an aromatic or non-aromatic ring systemwhich replaces an available hydrogen on the ring system. Ring systemsubstituents may be the same or different, each being independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, aryl,heteroaryl, -alkylene-aryl, -alkylene-heteroaryl,-alkenylene-heteroaryl, -alkynylene-heteroaryl, hydroxy, hydroxyalkyl,haloalkyl, —O-alkyl, —O-haloalkyl, -alkylene-O-alkyl, aralkoxy, acyl,aroyl, halo, nitro, cyano, carboxy, —C(O)O-alkyl, —C(O)O-aryl,—C(O)O-alkylene-aryl, —S(O)-alkyl, —S(O)₂-alkyl, —S(O)-aryl,—S(O)₂-aryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —S-alkyl, —S-aryl,—S-heteroaryl, —S-alkylene-aryl, —S-alkylene-heteroaryl, cycloalkyl,heterocycloalkyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl,—C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl), —N(Y¹)(Y²),-alkyl-N(Y¹)(Y²), —C(O)N(Y¹)(Y²) and —S(O)₂N(Y¹)(Y²), wherein Y₁ and Y₂can be the same or different and are independently selected from thegroup consisting of hydrogen, alkyl, aryl, cycloalkyl, and-alkylene-aryl. The term “ring system substituent” may also mean asingle moiety which simultaneously replaces two available hydrogens ontwo adjacent carbon atoms (one H on each carbon) on a ring system.Examples of such moiety are methylenedioxy, ethylenedioxy, —C(CH₃)₂— andthe like which form moieties such as, for example:

“Halo” means —F, —Cl, —Br or —I. In one embodiment, halo refers to —F,—Cl or —Br.

The term “haloalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a halogen. In one embodiment, a haloalkyl grouphas from 1 to 6 carbon atoms. In another embodiment, a haloalkyl groupis substituted with from 1 to 3 F atoms. Non-limiting examples ofhaloalkyl groups include —CH₂F, —CHF₂, —CF₃, —CH₂Cl and —CCl₃.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃. The term “alkoxy” as used herein, refers to an —O-alkylgroup, wherein an alkyl group is as defined above. Non-limiting examplesof alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy and t-butoxy. An alkoxy group is bonded via its oxygen atom.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of the compound afterbeing isolated from a synthetic process (e.g., from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of the compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al., Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula (I), its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g., a drugprecursor) that is transformed in vivo to yield a Pyrimidine Derivativeor a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood.

If a Pyrimidine Derivative or a pharmaceutically acceptable salt,hydrate or solvate of the compound contains a carboxylic acid functionalgroup, a prodrug can comprise an ester formed by the replacement of thehydrogen atom of the acid group with a group such as, for example,(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Pyrimidine Derivative contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkyl, α-amino(C₁-C₄)alkylene-aryl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate), and the like.

If a Pyrimidine Derivative incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl,—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylaminomorpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of solvates includeethanolates, methanolates, and the like. A “hydrate” is a solvatewherein the solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira at al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTechours., 5(1), article 12 (2004); and A. L. Binghamet al, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The Pyrimidine Derivatives can form salts which are also within thescope of this invention. Reference to a Pyrimidine Derivative herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when aPyrimidine Derivative contains both a basic moiety, such as, but notlimited to a pyridine or imidazole, and an acidic moiety, such as, butnot limited to a carboxylic acid, zwitterions (“inner salts”) may beformed and are included within the term “salt(s)” as used herein. In oneembodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salt. In another embodiment, the salt isother than a pharmaceutically acceptable salt. Salts of the compounds ofthe Formula (I) may be formed, for example, by reacting a PyrimidineDerivative with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, t-butyl amine, choline, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy group of a hydroxyl compound, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (for example, methyl, ethyl,n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (forexample, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl(for example, phenoxymethyl), aryl (for example, phenyl optionallysubstituted with, for example, halogen, C₁₋₄alkyl, or C₁₋₄alkoxy oramino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (forexample, methanesulfonyl); (3) amino acid esters (for example, L-valylor L-isoleucyl); (4) phosphonate esters and (5) mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di (C₆₋₂₄)acyl glycerol.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Sterochemically pure compounds may also be prepared by using chiralstarting materials or by employing salt resolution techniques. Also,some of the Pyrimidine Derivatives may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the Pyrimidine Derivatives may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, hydrates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, ifa Pyrimidine Derivative incorporates a double bond or a fused ring, boththe cis- and trans-forms, as well as mixtures, are embraced within thescope of the invention. In addition, all keto-enol and imine-enamineforms of the compounds are included in the invention.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled Pyrimidine Derivatives (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. In one embodiment, tritiated (i.e., ³H) andcarbon-14 (i.e., ¹⁴C) isotopes are employed for their ease ofpreparation and detectability. In another embodiment, substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements). In oneembodiment, a Pyrimidine Derivative has one or more of its hydrogenatoms replaced with a deuterium atom.

Isotopically labelled compounds of Formula (I) can generally be preparedby following procedures analogous to those disclosed in the Schemesand/or in the Examples herein below, by substituting an appropriateisotopically labelled reagent for a non-isotopically labelled reagent.

Polymorphic forms of the Pyrimidine Derivatives, and of the salts,solvates, hydrates, esters and prodrugs of the Pyrimidine Derivatives,are intended to be included in the present invention.

The following abbreviations are used below and have the followingmeanings: AcOH is acetic acid, Boc or BOC is —C(O)O-(t-butyl), n-BuLi isn-butyllithium, t-butyl is tertiary butyl, DAST is diethylaminosulfurtrichloride, dba is dibenzylidene acetone, DCE is dichloroethane, DCM isdichloromethane, DIAD is diisopropylazodicarboxylate, DIPEA and DIEAeach refer to diisopropylethylamine, DMEM is Dulbecco's modified eaglemedium, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, dppf is1,1′-bis(diphenylphosphino)ferrocene, EDC is1-(dimethylaminopropyl)-3-ethylcarbodiimide, EtOAc is ethyl acetate,EtOH is ethanol, Et₃N is triethylamine, EtNH₂ is ethylamine, HOBt is1-hydroxy-benzotriazole, LCMS is liquid chromatography massspectrometry, LDA is lithium diisopropylamide, mCPBA ismeta-chloroperoxybenzoic acid, MeOH is methanol, NaOEt is sodiumethoxide, NaOtBu is sodium t-butoxide, NMM is N-methylmorpholine, NMR isnuclear magnetic resonance, Ph is phenyl, PhMe is toluene, PLC ispreparative thin-layer chromatography, PS-EDC is polystyrenefunctionalized with EDC—available from Polymer Laboratories, PS-DIEA ispolystyrene functionalized with disopropylethylamine, TBAF istetra-n-butyl-ammonium fluoride, THF is tetrahydrofuran, and TLC isthin-layer chromatography.

The Pyrimidine Derivatives of Formula (I)

The present invention provides Pyrimidine Derivatives of Formula (I):

and pharmaceutically acceptable salts, solvates, esters, prodrugs andstereoisomers thereof, wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R⁴,R⁵, A, W, Q, Y, Z, n and p are defined above for the compounds offormula (I).

In one embodiment, R¹ is H

In another embodiment, R¹ is alkyl.

In another embodiment, R¹ is halo.

In still another embodiment, R¹ is —O-alkyl.

In another embodiment, R¹ is H, methyl, methoxy or F.

In another embodiment, R¹ is methyl, methoxy or F.

In yet another embodiment, R¹ is methyl.

In another embodiment, R¹ is methoxy.

In a further embodiment, R¹ is F.

In one embodiment, R^(2a) is H.

In another embodiment, R^(2a) is alkyl.

In another embodiment, R^(2a) and R^(2b) combine to form —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂OCH₂—.

In another embodiment, R^(2a) and R^(2b) combine to form —CH₂CH₂—.

In one embodiment, R^(2b) is. H.

In another embodiment, R^(2b) is alkyl.

In another embodiment, R^(2a) and R^(2b) are each H.

In one embodiment, R^(3a) is H.

In another embodiment, R^(3a) is alkyl.

In another embodiment, R^(3a) and R^(3b) combine to form —CH₂CH₂—,—CH₂CH₂CH₂— or —CH₂OCH₂—.

In another embodiment, R^(3a) and R^(3b) combine to form —CH₂CH₂—.

In one embodiment, R^(3b) is H.

In another embodiment, R^(3b) is alkyl.

In another embodiment, R^(3a) and R^(3b) are each H.

In a further embodiment, each occurrence of R^(2a), R^(2b), R^(3a) andR^(3b) is H.

In another embodiment, R^(2a) and R^(2b) combine to form —CH₂CH₂—, andR^(3a) and R^(3b) combine to form —CH₂CH₂—.

In one embodiment, R⁴ is alkyl.

In another embodiment, R⁴ is cycloalkyl.

In another embodiment, R⁴ is haloalkyl.

In still another embodiment, R⁴ is aryl.

In another embodiment, R⁴ is -alkylene-aryl.

In yet another embodiment, R⁴ is heteroaryl.

In one embodiment, R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl,pyridyl or phenyl, where a pyridyl or phenyl group can be optionallysubstituted with one or more groups, which can be the same or different,and which are selected from halo and haloalkyl.

In another embodiment, R⁴ is isopropyl.

In one embodiment, R⁵ is alkyl.

In another embodiment, R⁵ is cycloalkyl.

In another embodiment, R⁵ is haloalkyl.

In still another embodiment, R⁵ is -alkylene-aryl.

In another embodiment, R⁵ is —N(alkyl)₂.

In another embodiment, R⁵ is alkenyl

In one embodiment, R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃,benzyl, —N(CH₃)₂ or allyl.

In another embodiment, R⁵ is methyl.

In one embodiment, A is a bond and Q is —N—.

In another embodiment, A is —N(R⁶)— and Q is —CH—.

In another embodiment, A is —NH— and Q is —CH—.

In still another embodiment, A is —N(alkyl)- and Q is —CH—.

In another embodiment, A is —N(CH₃)— and Q is —CH—.

In one embodiment, Q is —N—.

In another embodiment, Q is —CH—.

In one embodiment, W is —C(O)O—.

In another embodiment, W is —C(O)—.

In another embodiment, W is —S(O)₂—.

In one embodiment, Y is —O— and Z is —CH—.

In another embodiment, Y is —NH— and Z is —CH—,

In another embodiment, Y is —S— and Z is —CH—.

In still another embodiment, Y is —CH₂— and Z is —N—.

In another embodiment, Y is a bond and Z is —N—.

In one embodiment, Z is —N—.

In another embodiment, Z is —CH—.

In one embodiment, each occurrence of n is 1.

In another embodiment, each occurrence of p is 1.

In another embodiment, one occurrence of p is 1 and the other occurrenceof p is 2.

In still another embodiment, each occurrence of n is 1 and eachoccurrence of p is 1.

In another embodiment, each occurrence of n is 1, one occurrence of p is1 and the other occurrence of p is 2.

In one embodiment, for the compounds of formula (Ia), W is —C(O)O— andR⁴ is alkyl.

In another embodiment, for the compounds of formula (Ia), W is —C(O)—and R⁴ is aryl, heteroaryl or -alkylene-aryl.

In another embodiment, for the compounds of formula (Ia), W is —S(O)₂—and R⁴ is alkenyl, cycloalkyl or —N(alkyl)₂.

In one embodiment, R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl,pyridyl or phenyl, where a pyridyl or phenyl group can be optionallysubstituted with one or more groups, which can be the same or different,and which are selected from halo and haloalkyl; and R⁵ is methyl,isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ or allyl.

In another embodiment, R¹ is methyl, methoxy or F; R⁴ is isopropyl,allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridylor phenyl group can be optionally substituted with one or more groups,which can be the same or different, and which are selected from halo andhaloalkyl; and R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃,benzyl, —N(CH₃)₂ or allyl.

In another embodiment, R¹ is methyl, methoxy or F; R⁴ is isopropyl,allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridylor phenyl group can be optionally substituted with one or more groups,which can be the same or different, and which are selected from halo andhaloalkyl; R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl,—N(CH₃)₂ or allyl; and Y is —O—.

In still another embodiment, R¹ is methyl, methoxy or F; R⁴ isisopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, wherea pyridyl or phenyl group can be optionally substituted with one or moregroups, which can be the same or different, and which are selected fromhalo and haloalkyl; R⁵ is methyl, isopropyl, cyclopropyl, ethyl,—CH₂CF₃, benzyl, —N(CH₃)₂ or allyl; Y is —O—; and W is —C(O)O—.

In another embodiment, R¹ is methyl, methoxy or F; R⁴ is isopropyl,allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridylor phenyl group can be optionally substituted with one or more groups,which can be the same or different, and which are selected from halo andhaloalkyl; R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl,—N(CH₃)₂ or allyl; Y is —O—; and W is —C(O)—.

In yet another embodiment, R¹ is methyl, methoxy or F; R⁴ is isopropyl,allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridylor phenyl group can be optionally substituted with one or more groups,which can be the same or different, and which are selected from halo andhaloalkyl; R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl,—N(CH₃)₂ or allyl; Y is —O—; and W is —S(O)₂—.

In one embodiment, the present invention provides compounds of Formula(I), wherein variables R¹, R^(2a), R^(2b), R^(3a), R^(3b), R⁴, R⁵, A, W,O, Y, Z, n and p are selected independently of each other.

In one embodiment, a compound of formula (I) is in purified form.

In one embodiment, the compounds of formula (I) have the formula.

wherein:

R¹ is H, alkyl, —O-alkyl or halo;

R⁴ is alkyl, cycloalkyl, haloalkyl, aryl, -alkylene-aryl or heteroaryl,wherein an aryl or heteroaryl group can be optionally substituted withone or more groups, which can be the same or different, and are selectedfrom alkyl, halo, haloalkyl, —O-alkyl, —CN and —S(O)₂-alkyl;

R⁵ is alkyl, cycloalkyl, haloalkyl, -alkylene-aryl, alkenyl or—N(alkyl)₂;

W is —C(O)O—, —C(O)— or —S(O)₂—; and

Y is —O—, —S— or —NH—.

In one embodiment, for the compounds of formula (Ia), R¹ is methyl,methoxy or F.

In another embodiment, for the compounds of formula (Ia), R⁴ isisopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, wherea pyridyl or phenyl group can be optionally substituted with one or moregroups, which can be the same or different, and which are selected fromhalo and haloalkyl.

In another embodiment, for the compounds of formula (Ia), R⁴ isisopropyl.

In still another embodiment, for the compounds of formula (Ia), R⁵ ismethyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ orallyl.

In another embodiment, for the compounds of formula (Ia), R⁵ is methyl.

In one embodiment, for the compounds of formula (Ia), W is —C(O)O—.

In another embodiment, for the compounds of formula (Ia), W is —S(O)₂—.

In another embodiment, for the compounds of formula (Ia), W is —C(O)—.

In one embodiment, for the compounds of formula (Ia), Y is —O—.

In one embodiment, for the compounds of formula (Ia), W is —C(O)O— andR⁴ is alkyl.

In another embodiment, for the compounds of formula (Ia), W is —C(O)—and R⁴ is aryl, heteroaryl or -alkylene-aryl.

In another embodiment, for the compounds of formula (Ia), W is —S(O)₂—and R⁴ is alkenyl, cycloalkyl or —N(alkyl)₂.

In one embodiment, for the compounds of formula (Ia), R¹ is methyl,methoxy or F; R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl,pyridyl or phenyl, where a pyridyl or phenyl group can be optionallysubstituted with one or more groups, which can be the same or different,and which are selected from halo and haloalkyl; and R⁵ is methyl,isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ or allyl.

In another embodiment, for the compounds of formula (Ia), R¹ is methyl,methoxy or F; R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl,pyridyl or phenyl, where a pyridyl or phenyl group can be optionallysubstituted with one or more groups, which can be the same or different,and which are selected from halo and haloalkyl; R⁵ is methyl, isopropyl,cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ or allyl; and Y is —O—.

In another embodiment, for the compounds of formula (Ia), R¹ is methyl,methoxy or F; R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl,pyridyl or phenyl, where a pyridyl or phenyl group can be optionallysubstituted with one or more groups, which can be the same or different,and which are selected from halo and haloalkyl; R⁵ is methyl, isopropyl,cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ or allyl; Y is —O—; and Wis —C(O)O—.

In still another embodiment, for the compounds of formula (Ia), R¹ ismethyl, methoxy or F; R⁴ is isopropyl, allyl, cyclopropyl, t-butyl,ethyl, pyridyl or phenyl, where a pyridyl or phenyl group can beoptionally substituted with one or more groups, which can be the same ordifferent, and which are selected from halo and haloalkyl; R⁵ is methyl,isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ or allyl; Y is—O—; and W is —C(O)—.

In another embodiment, for the compounds of formula (Ia), R¹ is methyl,methoxy or F; R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl,pyridyl or phenyl, where a pyridyl or phenyl group can be optionallysubstituted with one or more groups, which can be the same or different,and which are selected from halo and haloalkyl; R⁵ is methyl, isopropyl,cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ or allyl; Y is —O—; and Wis —S(O)₂—.

Non-limiting examples of the Pyrimidine Derivatives include, but are notlimited to compounds 1-34, depicted in the table below:

Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

and pharmaceutically acceptable salts, solvates, esters, prodrugs andstereoisomers thereof.

Methods for Making the Pyrimidine Derivatives

Methods useful for making the Pyrimidine Derivatives are set forth inthe Examples below and generalized in Schemes 1-4. Alternative syntheticpathways and analogous structures will be apparent to those skilled inthe art of organic synthesis.

Scheme 1 shows methods useful for making the compounds of formula F,which correspond to the Compounds of Formula (I) where Y is —O— and Z is—CH—.

wherein Y is —O—, Z is —CH—, and R¹, R^(2a), R^(2b), R^(3a), R^(3b), R⁴,R⁵, A, Q, W, n and p are defined above for the Compounds of Formula (I).

Dichloropyrimidine (A) can first be reacted with either a compound offormula B or formula C, to provide the intermediate compounds offormulas D and E, respectively. Reaction of a compound of formula A witha compound of formula B in the presence of a base such as NaH or KO-tBuprovides the ether intermediates of formula D. Similarly, reaction of Awith a compound of formula C provides the ether intermediates of formulaE. The compounds of formula F, which correspond to the Compounds ofFormula (I) where Y is —O— and Z is —CH—, can be obtained by eitherreacting a compound of formula D with a compound of formula C or byreacting a compound of formula E with a compound of formula B.

Schemes 2(a) and 2(b) presents variants of a linear synthesis of theCompounds of Formula (I) which provide the option of using an amineprotecting group such as Boc to protect the —W—R⁴ position and allow forthe —W—R⁴ group to be installed at any point during the synthesis.

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R⁴, R⁵, A, Q, W, Y, Z, n andp are defined above for the Compounds of Formula (I).

According to Scheme 2(a), the Boc protecting group of compound offormula G can be removed early in the synthesis using, for example,acidic reagents such as trifluoroacetic acid or HCl/dioxane, to providethe amine compounds of formula H. The amine group of a compound offormula H can then be functionalized with a —W—R⁴ group in an earlystage in the synthesis using methods well-known in the art of organicsynthesis (such as reacting with an appropriate chloroformate, sulfonylchloride, or acid chloride reagent), to provide the intermediates offormula E. The compounds of formula E can then be further elaborated toprovide the compounds of formula (I) using the method described inScheme 1.

According to the method described in Scheme 2(b), the Boc protectinggroup can remain intact until the stage in the synthesis wherein theintermediates of formula J are prepared. The Boc group can then beremoved at this later stage and the —W—R⁴ group can be introduced at theend of the synthetic route, to provide the Compounds of Formula (I).Other protective groups, such as carbobenzyloxy, may also be employed,with deprotection under the relevant conditions. In the case where Q is—CH— and A is N(R⁶), an R⁶ alkyl group may be introduced by reaction ofthe compound where A is NH using an alkyl halide and a base such as NaH.

Scheme 3 shows a method useful for making the compounds of formula L,which correspond to the Compounds of Formula (I) where Y is a bond and Zis —N—.

wherein Y is a bond, Z is —N—, and R¹, R^(2a), R^(2b), R^(3a), R^(3b),R⁴, R⁵, A, Q, W, n and p are defined above for the Compounds of Formula(I).

A compound of formula E can be reacted with an amine of formula K in thepresence of a non-nucleophilic base such as DIPEA in DMF to provide thecompounds of formula L, which correspond to the Compounds of Formula (I)where Y is a bond and Z is —N—.

Scheme 4 shows a method useful for making the compounds of formula Q,which correspond to the Compounds of Formula (I) where Y is —CH₂— and Zis —N—.

wherein Y is —CH₂—, Z is —N—, and R¹, R^(2a), R^(2b), R^(3a), R^(3b),R⁴, R⁵, A, Q, W, n and p are defined above for the Compounds of Formula(I).

An ester of formula M can be condensed with an alcohol of formula Cusing, for example, triphenylphosphine and an azodicarboxylate ester, toprovide the ether compounds of formula N. The ester group of a compoundof formula N can then be reduced using NaBH₄, for example, to providethe hydroxy compounds of formula 0, which are subsequently chlorinatedusing methanesulfonyl chloride or thionyl chloride to provide the chlorocompounds of formula P. Reaction of the compounds of formula P with anamine of formula K in the presence of a base, such as DIPEA and KC inDMF at elevated temperature, provides the compounds of formula Q, whichcorrespond to the Compounds of Formula (I) where Y is —CH₂— and Z is—N—.

The methodology set forth above in Schemes 1-4 also allows forincorporation of isotopes, particularly those of hydrogen and carbon, inappropriate starting materials to provide isotopically labeled Compoundsof Formula (I). Alternatively, isotopes may be introduced at the finalstage by well-known methods such as the replacement of halogen withisotopes of hydrogen.

The starting materials and reagents depicted in Schemes 1-4 are eitheravailable from commercial suppliers such as Sigma-Aldrich (St. Louis,Mo.) and Acros Organics Co. (Fair Lawn, N.J.), or can be prepared usingmethods well-known to those of skill in the art of organic synthesis.

One skilled in the art will recognize that the synthesis of PyrimidineDerivatives may require the need for the protection of certainfunctional groups (i.e., derivatization for the purpose of chemicalcompatibility with a particular reaction condition). Suitable protectinggroups for the various functional groups of the Pyrimidine Derivativesand methods for their installation and removal may be found in Greene etal., Protective Groups in Organic Synthesis, Wiley-Interscience, NewYork, (1999).

EXAMPLES

The following examples exemplify illustrative examples of compounds ofthe present invention and are not to be construed as limiting the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

General Methods

Solvents, reagents, and intermediates that are commercially availablewere used as received. Reagents and intermediates that are notcommercially available were prepared in the manner described below. ¹HNMR spectra were obtained on a Gemini AS-400 (400 MHz) and are reportedas ppm down field from Me₄Si with number of protons, multiplicities, andcoupling constants in Hertz indicated parenthetically. Where LC/MS dataare presented, analyses was performed using an Applied BiosystemsAPI-100 mass spectrometer and Shimadzu SCL-10A LC column: Altechplatinum C18, 3 micron, 33 mm×7 mm ID; gradient flow: 0 min—10% CH₃CN, 5min—95% CH₃CN, 7 min—95% CH₃CN, 7.5 min—10% CH₃CN, 9 min—stop. Theobserved parent ions are given.

Example 1 Preparation of Compound 1

Step A—Synthesis of Compound 1A

N-Boc-4-piperidinol (2.50 g, 12.4 mmol) was taken up in THF (30 mL) andthe resulting solution was cooled to 0° C. NaH (60% in oil, 0.60 g, 15mmol) was added to the cooled solution and the resulting reaction wasallowed to stir for 20 minutes at 0° C. 4,6-Dichloro-5-methylpyrimidine(2.00 g, 12.2 mmol) was then added, and the resulting reaction wasallowed to stir for 1 hour at 0° C., then warmed to room temperature andallowed to stir at this temperature for an additional 18 hours. Thereaction mixture was diluted with ether (10 mL), the resulting solutionwas filtered, and the filtrate was concentrated in vacuo to provideCompound 1A as a yellow solid.

Step B—Synthesis of Compound 1B

Compound 1A (0.100 g, 0.31 mmol) in CH₂Cl₂ (4 mL) was treated withtrifluoroacetic acid (2.0 mL, 27 mmol). The resulting reaction wasallowed to stir for 30 minutes, then the reaction mixture wasconcentrated in vacuo. The resulting residue was purified using PLC(eluant 5% of 7M NH₃/MeOH in CH₂Cl₂) to provide Compound 1B as acolorless film.

Step C—Synthesis of Compound 1C

To a solution of compound 1B (0.064 g, 0.28 mmol) in EtOAc (4 mL) wasadded N-methylmorphiline (0.031 mL, 0.28 mmol), followed by isopropylchloroformate (1.0M in toluene, 0.28 mL, 0.28 mmol). The resultingreaction was allowed to stir for 40 minutes, then was concentrated invacuo and the residue obtained was purified using PLC to provideCompound 1C as a colorless oil.

Step D—Synthesis of Compound 1D

Compound 1C (0.060 g, 0.19 mmol) was combined with N-Boc-4-piperidinol(0.052 g, 0.26 mmol) and NaO-tBu (0.024 g, 0.25 mmol) in DMF (3 mL) andthe resulting reaction heated to 100° C. and allowed to stir at thistemperature for 20 hours. The reaction mixture was cooled to roomtemperature, concentrated in vacuo, and the resulting residue waspurified using PLC (eluant MeOH/CH₂Cl₂) to provide Compound 1D as acolorless oil.

Step E—Synthesis of Compound 1E

Using the method described in Step B of this Example, Compound 1D wasconverted to Compound 1E as a colorless film.

Step F Synthesis of Compound 1

To a solution of Compound 1E (0.023 g, 0.061 mmol) in CH₂Cl₂ (2 mL) wasadded Et₃N (0.011 mL, 0.079 mmol) followed by methanesulfonyl chloride(0.0056 mL, 0.073 mmol), and the resulting reaction was allowed to stirfor 10 minutes. The reaction mixture was concentrated in vacuo and theresulting residue was purified using PLC to provide Compound 1 as awhite solid, MS: m/e 457 (M+1).

Example 2 Preparation of Compound 2

Step A—Synthesis of Compound 2A

Compound 1C (0.098 g, 0.31 mmol) was combined withN-Boc-4-aminopiperidine (0.085 g, 0.042 mmol), NaO-tBu (0.042 g, 0.44mmol), (+)-BINAP (0.012 g, 0.02 mmol) and Pd₂ dba₃ (0.004 g, 0.006 mmol)in toluene (3 mL). The resulting reaction was heated to 100° C. andallowed to stir at this temperature for 90 hours. The reaction mixturewas then cooled to room temperature, concentrated in vacuo and purifiedusing PLC to provide Compound 2A as a colorless film.

Step B—Synthesis of Compound 2B

Compound 2A was converted to 2B using the method described in Example 1,Step B.

Step C—Synthesis of Compound 2

Compound 2B was converted to Compound 2 using the method described inExample 1, Step F. Compound 2 was obtained as a white solid, MS: m/e 456(M+1).

Example 3 Preparation of Compound 3

Using the method described in Example 1, Step F, and usingpropane-2-sulfonyl chloride, compound 1E was converted to compound 3, ascolorless film, MS: m/e 485 (M+1).

Using this method and substituting the appropriate sulfonyl chloride,the following compounds of the present invention were prepared:

Compound MS No. Structure (m/e) 4

483 5

471 6

525 7

533 8

486 9

525 11

483

Example 4 Preparation of Compound 13

Step A—Synthesis of Compound 4A

Using the method described in Example 1, Step D, Compound 1C was reactedwith N-Boc-4-hydroxyazepane to provide Compound 4A as a yellow oil.

Step B—Synthesis of Compound 4B

Using the method described in Example 1, Step 2, Compound 4A wasconverted to Compound 4B as a colorless oil.

Step C—Synthesis of Compound 13

Using the method described in Example 1, Step F, Compound 4B wasconverted to Compound 13 as a colorless oil, MS: m/e 471 (M+1).

Example 5 Preparation of Compound 14

Step A—Synthesis of Compound 5A

Using the method described in Example 1, Step D, Compound 1C was reactedwith N-Boc-trans-4-aminocyclohexanol to provide Compound 5A as acolorless oil.

Step B—Synthesis of Compound 5B

Using the method described in Example 1, Step B, Compound 5A wasconverted to Compound 5B as a colorless oil.

Step C Synthesis of Compound 14

Using the method described in Example 1, Step F, Compound 5B wasconverted to Compound 14 as a colorless oil, MS: m/e 471 (M+1).

Example 6 Preparation of Compound 15

To a solution of Compound 14 (0.006 g, 0.013 mmol) in DMF (2 mL) wasadded NaH (60% in oil, 0.0008 g, 0.02 mmol), followed by iodomethane(0.004 mL, 0.06 mmol). The resulting reaction was allowed to stir for 20hours, then the reaction mixture was concentrated in vacuo. The residueobtained was purified using PLC to provide Compound 15 as a white film,MS: m/e 485 (M+1).

Example 7 Preparation of Compound 16

Compound 1A was reacted with N-(methanesulfonyl)-4-hydroxypiperidineusing the method described in Example 1, Step D, to provide Compound 16as a white solid. MS: m/e 471 (M+1).

Example 8 Preparation of Compound 17

Using the methods described in Example 1, Steps A-F,4,6-Dichloro-5-methoxypyrimidine was converted to Compound 17 as acolorless oil. MS: m/e 473 (M+1).

Example 9 Preparation of Compound 18

Step A—Synthesis of Compound 9A

Using the methods described in Example 1, Step B, Compound 16 wasconverted to Compound 9A.

Step B—Synthesis of Compound 18

Compound 9A was reacted with allylsulfonyl chloride using the methoddescribed in Example 1, Step F, to provide Compound 18 as a white solid,MS: m/e 475 (M+1).

Using this method and substituting the appropriate sulfonyl chloride,chloroformate, or add chloride, the following compounds of the presentinvention were prepared from Compound 9A:

Compound MS No. Structure (m/e) 19

475 20

478 21

443 22

489 23

493 24

476 25

511 26

543 27

509, 511

Example 10 Preparation of Compound 28

Step A—Synthesis of Compound 10A

N-Methanesulfonyl)-4-piperidinol (0.097 g, 0.544 mmol),4,6-dichloro-5-methylpyrimidine (0.080 g, 0.49 mmol) and NaH (60% inoil, 0.024 g, 0.58 mmol) were combined in THF (2 mL). The resultingreaction was heated to 40° C. and allowed to stir at this temperaturefor 18 hours, then the reaction mixture was concentrated in vacuo. Theresidue obtained was purified using PLC (20% acetone/hexane) to provideCompound 10A as a yellow oil.

Step B—Synthesis of Compound 10B

Boc-nortropanone (0.360 g, 1.6 mmol) was combined with NaBH₄ (0.090 g,2.4 mmol) in THF (5 mL). The resulting reaction was heated to 60° C. andallowed to stir at this temperature for 3 hours, then cooled to 0° C.,and partitioned between ether and satd. Aqueous NaHCO₃ solution. Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuo toprovide Compound 10B, a mixture of exo and endo isomers, as a yellowoil, which was used without further purification.

Step C—Synthesis of Compound 28

Compound 10A (0.046 g, 0.15 mmol), compound 10B (0.047 g, 0.21 mmol),and NaH (60% in oil, 0.010 g, 0.25 mmol) were combined in DMF (1.5 mL).The resulting reaction mixture was heated to 100° C. and allowed to stirat this temperature for 18 hours, then cooled to room temperature. Thereaction mixture was then concentrated in vacuo and the resultingresidue was purified using PLC (20% acetone/hexane) to provide Compound28, as a white solid (4:1 mixture of exo and endo isomers). MS: m/e 497(M+1).

Example 11 Preparation of Compound 29

Step A—Synthesis of Compound 11A

Compound 10B was purified using flash column chromatography on silicagel (30-60% EtOAc/hexane) to provide exo isomer 11A as theslower-eluting material.

Step B—Synthesis of Compound 11B

Compounds 10A and 11A were reacted according to the method described inExample 10, Step C, using NaO-tBu as base (microwave heating at 160° C.for 8 minutes) to provide Compound 11B as a yellow solid, which was usedwithout further purification.

Step C Synthesis of Compound 29

Compound 11B (0.065 g, 0.13 mmol) was taken up in 4.0M HCl/dioxane (2.0mL). The reaction mixture was allowed to stir for 2 hours, then wasconcentrated in vacuo and the resulting residue was reacted withcyclopropanesulfonyl chloride using the method described in Example 1,Step F, to provide Compound 29 as an off-white solid, MS: m/e 501 (M+1).

Example 12 Preparation of Compound 30

Step A—Synthesis of Compound 12A

To 1,4-anhydroerythritol (5.00 g, 48 mmol) in water (70 mL) was addedNalO₄ (5.10 g, 24 mmol). The resulting reaction was allowed to stir for18 hours, then MeCN (70 mL) was added. The resulting reaction wasallowed to stir for 30 minutes, then the reaction mixture was filteredand concentrated in vacuo to provide Compound 12A, which was usedwithout further purification.

Step B—Synthesis of Compound 128

To a solution of Compound 12A in acetone-1,3-dicarboxylic acid (7.0 g,48 mmole) and conc. HCl (2.5 mL), was added benzylamine (6.14 mL, 66mmol) via dropwise addition. The resulting reaction was allowed to stirfor 1.5 hours, then the reaction was heated to 50° C. and allowed tostir at this temperature for 5 hours. The reaction mixture was cooled to0° C., basified to pH 10 with 1N NaOH, and extracted with ether. Theorganic extract was dried (K₂CO₃), filtered and concentrated in vacuo,and the residue obtained was purified using flash chromatography onsilica to provide Compound 12B as an oil.

Step C—Synthesis of Compound 12C

To a solution of Compound 12B (8.75 g, 38 mmol) in 1N HCl (40 mL) andEtOH (40 mL), was added 10% Pd/C (1.00 g). The mixture was hydrogenatedat 50 psi for 18 hours, then filtered, and the filtrate was concentratedin vacuo to provide Compound 12C as a brown solid, which was usedwithout further purification.

Step D—Synthesis of Compound 12D

To a solution of Compound 12C (3.90 g, 22 mmol) in EtOH (40 mL) wasadded Boc₂O (5.30 g, 24 mmol) and Et₃N (4.60 mL, 33 mmol) and theresulting reaction was allowed to stir for 3 hours. Water (100 mL) wasthen added to the reaction mixture and the resulting solution wasextracted with EtOAc. The organic extract was dried (MgSO₄), filteredand concentrated in vacuo to provide Compound 12D as a yellow solid,which was used without further purification.

Step E—Synthesis of Compound 12E

To a solution of Compound 12D in THF (50 mL) was added NaBH₄ (1.50 g, 39mmol), the resulting reaction was allowed to stir for 2 hours, then MeOH(10 mL) was added. The resulting solution was allowed to stir for 1hour, then water (100 mL) was added and the resulting solution wasextracted with ether. The organic extract was dried (MgSO₄), filteredand concentrated in vacuo to provide Compound 12E, which was usedwithout further purification.

Step F Synthesis of Compound 30

Compounds 10A and 12E were reacted according to the method described inExample 11, Step B, to provide Compound 30 as a yellow solid, MS: m/e513 (M+1).

Example 13 Preparation of Compound 31

Step A—Synthesis of Compound 13A

N-Boc-4-(methanesulfonyloxy)piperidine (2.79 g, 10.0 mmol) and potassiumthioacetate (1.71 g, 15 mmol) were combined in DMF (20 mL) and theresulting reaction was heated to 65° C. and allowed to stir at thistemperature for 18 hours. The reaction mixture was cooled to roomtemperature and partitioned between ether and water. The organic phasewas collected, sequentially washed with water, 1N aqueous NaHCO₃, and 1NHCl, then dried (MgSO₄), filtered and concentrated in vacuo to provideCompound 13A as an orange oil, which was used without furtherpurification.

Step B—Synthesis of Compound 13B

To a solution of Compound 13A (0.50 g, 1.9 mmol) in MeOH (6 mL) wasadded 1.0N NaOH (2.9 mL). The resulting reaction was allowed to stir 2hours, then 1.0N HCl (2.9 mL) was added and the resulting solution wasconcentrated in vacuo. The residue obtained was taken up in EtOH (15 mL)and filtered and the filtrate was concentrated in vacuo to provideCompound 13B as a brown oil, which was used without furtherpurification.

Step C—Synthesis of Compound 13C

Compound 13B (0.150 g, 0.48 mmol) and Compound 1C were combined withK₂CO₃ (0.099 g, 0.72 mmol) in DMF (4 mL). The resulting reaction wasplaced under N₂ atmosphere, heated to 70° C. and allowed to stir at thistemperature for 90 hours. NaO-tBu (0.023 g, 0.24 mmol) was then addedand the resulting reaction was allowed to stir at reflux for anadditional 4 hours, then cooled to room temperature. The cooled reactionmixture was concentrated in vacuo, and the residue obtained was purifiedusing PLC to provide Compound 13C as a colorless oil.

Step D—Synthesis of Compound 31

Compound 13C was reacted according to the method described in Example11, Step C and the product obtained was purified using PLC to provide anamine intermediate as a colorless oil. This intermediate amine was thenreacted with methanesulfonyl chloride using the method described inExample 1, Step F, to provide Compound 31 as a white solid, MS: m/e 473(M+1).

Example 14 Preparation of Compound 32

Step A—Synthesis of Compound 14A

N-Boc-4-hydroxypiperidine (0.410 g, 2.04 mmol), ethyl6-hydroxy-5-methylpyrimidine-2-carboxylate (0.300 g, 1.64 mmol) andtriphenylphosphine (0.518 g, 1.98 mmol) were combined in THF (20 mL) andthe resulting solution was cooled to 0° C. Diethyl azodicarboxylate(0.311 mL, 1.98 mmol) was added slowly to the cooled solution and theresulting reaction was allowed to warm to room temperature on its ownwith stirring for 18 hours. The reaction mixture was then concentratedin vacuo and the residue obtained was purified using PLC to provideCompound 14A as a yellow oil.

Step B—Synthesis of Compound 14B

To a 0° C. solution of Compound 14A (0.110 g, 0.30 mmol) in MeOH (3 mL)was added NaBH₄ (0.059 g, 1.5 mmol) and the resulting reaction wasallowed to warm to room temperature on its own with stirring for 18hours. The reaction was then heated to 60° C. and allowed to stir atthis temperature for 1.5 hours, then concentrated in vacuo. The residueobtained was purified using PLC to provide Compound 14B as a colorlessoil.

Step C—Synthesis of Compound 14C

Compound 14B was converted to Compound 14C (colorless oil) using themethod described in Example 1, Step F.

Step D—Synthesis of Compound 32

Compound 14C (0.056 g, 0.16 mmol), 1-(methanesulfonyl)piperazine (0.033g, 0.20 mmol) and KI (0.0027 g, 0.016 mmol) were combined in DMF (4 mL)and the resulting reaction was heated to 110° C. and allowed to stir atthis temperature for 20 hours. The reaction mixture was then cooled toroom temperature, concentrated in vacuo, and the residue obtained waspurified using PLC to provide Compound 32 as a brown oil, MS: m/e 470(M+1).

Example 15 Preparation of Compound 33

Compound 1A (0.150 g, 0.46 mmol), 1-(methanesulfonyl)piperazine (0.092g, 0.56 mmol) and DIPEA (0.120 mL, 0.69 mmol) were combined in DMF (3mL). The resulting reaction was heated to 120° C. and allowed to stir atthis temperature for 18 hours. The reaction was then cooled to roomtemperature and concentrated in vacuo and the residue obtained waspurified using PLC (1% MeOH/CH₂Cl₂) to provide Compound 33 as acolorless oil. MS: m/e 456 (M+1).

Example 16 Preparation of Compound 34

Step A—Synthesis of Compound 16A

Compound 33 was converted to Compound 16A (as its hydrochloride salt)using the method described in Example 11, Step C.

Step B—Synthesis of Compound 34

Compound 16A was converted to Compound 34 (colorless oil) using themethod described in Example 1, Step C. MS: m/e 442 (M+1).

Example 17 Preparation of Compound 12

Step A—Synthesis of Compound 17A

4,6-dichloro-5-methylpyrimidine was reacted with 2 equivalents ofCompound 11A using the method described in Example 11, Step B to provideCompound 17A.

Step B Synthesis of Compound 12

Compound 17A was reacted using the method described in Example 11, StepC, to provide an intermediate compound which was subsequently convertedto Compound 12 (brown solid), using the method described in Example 11,Step D. MS: m/e 553 (M+1).

Example 18 Preparation of Compound 10

Step A—Synthesis of Compound 18A

4,6-dichloro-5-methoxypyrimidine was reacted with 2 equivalents ofCompound 11A using the method described in Example 11, Step B to provideCompound 18A.

Step B—Synthesis of Compound 10

Using the method described in Example 11, Step C, Compound 18A wasconverted to an intermediate compound which was subsequently convertedto Compound 10 as an off-white solid, using the method described inExample 11, Step D. MS: m/e 569 (M+1).

Example 19 Preparation of Compound 36

Step A—Synthesis of Compound 19A

2,2-6,6-Tetradeutero-4-hydroxypiperidine (prepared as described in J.Labelled Compounds Radiopharm. 2007, 137) was converted to Compound 19Ausing the method described in Example 12, Steps E-F.

Step B—Synthesis of Compound 36

Compound 19A was converted to Compound 36 using the method described inExample 1, Steps A-F, to provide, MS: m/e 561 (M+1).

Example 20 cAMP Assay

The ability of illustrative compounds of the invention to activateGPR119 and stimulate increases in cAMP levels was determined using theLANCE™ cAMP kit (Perkin Elmer). HEK293 cells expressing human GPR119were maintained in culture flasks at 37° C./5% CO₂ in DMEM containing10% fetal bovine serum, 100 U/ml Pen/Strep, and 0.5 mg/ml geneticin. Themedia was changed to Optimem and cells were incubated overnight at 37°C./5% CO₂. The Optimem was then aspirated and the cells were removedfrom the flasks using room temperature Hank's balanced saline solution(HBSS). The cells were pelleted using centrifugation (1300 rpm, 7minutes, room temperature), then resuspended in stimulation buffer(HBSS, 0.1% BSA, 5 mM HEPES, 15 μM RO-20) at 2.5×10⁶ cells/mL. AlexaFluor 647-anti CAMP antibody (1:100) was then added to the cellsuspension and incubated for 30 minutes. A representative PyrimidineDerivative (6 μl at 2× concentration) in stimulation buffer containing2% DMSO were then added to white 384 well Matrix plates. Cell suspensionmix (6 μl) was added to each well and incubated with the PyrimidineDerivative for 30 minutes. A cAMP standard curve was also created ineach assay according to the kit protocol. Standard concentrations ofcAMP in stimulation buffer (6 μl) were added to white 384 well plates.Subsequently, 6 μl of 1:100 anti-cAMP antibody was added to each well.Following the 30 minute incubation period, 12 μl of detection mix(included in kit) was added to all wells and incubated for 2-3 hours atroom temperature. Fluorescence was detected on the plates using anEnvision instrument. The level of cAMP in each well is determined byextrapolation from the cAMP standard curve.

Using this assay, EC₅₀ values for various illustrative PyrimidineDerivatives of the present invention were calculated and range fromabout 15 nm to about 3800 nM.

Example 21 Determination of the Effect of the Compounds of the Inventionin Oral Glucose Tolerance Test

Male C57Bl/6NCrl mice (6-8 week old) are used for this test and testanimals are first fasted overnight and then randomly dosed with eithervehicle (20% hydroxypropyl-β-cyclodextrin) or a representative compoundof the invention (at 3, 10 or 30 mg/kg) via oral gavage (n=8mice/group). Glucose is then administered to the animals 30 minutespost-dosing (3 g/kg p.o.). Blood glucose is measured prior toadministration of test compound and glucose, and at 20 minutes afterglucose administration using, for example, a hand-held glucometer.

Using this protocol, the effects of various Pyrimidine Derivatives ofthe present invention can be determined for their efficacy in loweringblood glucose levels after glucose challenge.

Uses of the Pyrimidine Derivatives

The Pyrimidine Derivatives are useful in human and veterinary medicinefor treating or preventing a Condition in a patient. In accordance withthe invention, the Pyrimidine Derivatives can be administered to apatient in need of treatment or prevention of a Condition.

Treatment of Obesity and Obesity-Related Disorders

The Pyrimidine Derivatives are useful for treating obesity or anobesity-related disorder.

Accordingly, in one embodiment, the invention provides methods fortreating obesity or an obesity-related disorder in a patient, whereinthe method comprises administering to the patient an effective amount ofone or more Pyrimidine Derivatives, or a pharmaceutically acceptablesalt, solvate, ester, prodrug or stereoisomer thereof.

Treatment of Diabetes

The Pyrimidine Derivatives are useful for treating diabetes in apatient. Accordingly, in one embodiment, the present invention providesa method for treating diabetes in a patient, comprising administering tothe patient an effective amount of one or more Pyrimidine Derivatives.

Non-limiting examples of diabetes treatable or preventable using thePyrimidine Derivatives include, type I diabetes (insulin-dependentdiabetes mellitus), type II diabetes (non-insulin dependent diabetesmellitus), gestational diabetes, autoimmune diabetes, insulinopathies,idiopathic type I diabetes (Type 1b), latent autoimmune diabetes inadults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes(YOAD), maturity onset diabetes of the young (MODY),malnutrition-related diabetes, diabetes due to pancreatic disease,diabetes associated with other endocrine diseases (such as Cushing'sSyndrome, acromegaly, pheochromocytoma, glucagonoma, primaryaldosteronism or somatostatinoma), type A insulin resistance syndrome,type B insulin resistance syndrome, lipatrophic diabetes, diabetesinduced by β-cell toxins, and diabetes induced by drug therapy (such asdiabetes induced by antipsychotic agents).

In one embodiment, the diabetes is type I diabetes.

In another embodiment, the diabetes is type II diabetes.

Treatment of a Diabetic Complication

The Pyrimidine Derivatives are useful for treating a diabeticcomplication in a patient. Accordingly, in one embodiment, the presentinvention provides a method for treating a diabetic complication in apatient, comprising administering to the patient an effective amount ofone or more Pyrimidine Derivatives.

Non-limiting examples of diabetic complications treatable or preventableusing the Pyrimidine Derivatives include diabetic cataract, glaucoma,retinopathy, aneuropathy (such as diabetic neuropathy, polyneuropathy,mononeuropathy, autonomic neuropathy, microaluminuria and progressivediabetic neuropathyl), nephropathy, gangrene of the feet, immune-complexvasculitis, systemic lupus erythematosus (SLE), atherosclerotic coronaryarterial disease, peripheral arterial disease, nonketotichyperglycemic-hyperosmolar coma, foot ulcers, joint problems, a skin ormucous membrane complication (such as an infection, a shin spot, acandidal infection or necrobiosis lipoidica diabeticorumobesity),hyperlipidemia, cataract, hypertension, syndrome of insulin resistance,coronary artery disease, a fungal infection, a bacterial infection, andcardiomyopathy.

Treatment of a Metabolic Disorder

The Pyrimidine Derivatives are useful for treating a metabolic disorder.Accordingly, in one embodiment, the invention provides methods fortreating a metabolic disorder in a patient, wherein the method comprisesadministering to the patient an effective amount of one or morePyrimidine Derivatives, or a pharmaceutically acceptable salt, solvate,ester, prodrug or stereoisomer thereof.

Non-limiting examples of metabolic disorders treatable include metabolicsyndrome (also known as “Syndrome X”), impaired glucose tolerance,impaired fasting glucose, hypercholesterolemia, hyperlipidemia,hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria,post-prandial lipidemia, a glycogen-storage disease, Gaucher's Disease,Tay-Sachs Disease, Niemann-Pick Disease, ketosis and acidosis.

In one embodiment, the metabolic disorder is hypercholesterolemia.

In another embodiment, the metabolic disorder is hyperlipidemia.

In another embodiment, the metabolic disorder is hypertriglyceridemia.

In still another embodiment, the metabolic disorder is metabolicsyndrome.

In a further embodiment, the metabolic disorder is low HDL levels.

Methods for Treating a Cardiovascular Disease

The Pyrimidine Derivatives are useful for treating or preventing acardiovascular disease in a patient. Accordingly, in one embodiment, thepresent invention provides a method for treating a cardiovasculardisease in a patient, comprising administering to the patient aneffective amount of one or more Pyrimidine Derivatives.

Non-limiting examples of cardiovascular diseases treatable orpreventable using the present methods include atherosclerosis,congestive heart failure, cardiac arrhythmia, myocardial infarction,atrial fibrillation, atrial flutter, circulatory shock, left ventricularhypertrophy, ventricular tachycardia, supraventricular tachycardia,coronary artery disease, angina, infective endocarditis, non-infectiveendocarditis, cardiomyopathy, peripheral artery disease, Reynaud'sphenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis,pulmonic stenosis and tricuspid stenosis.

In one embodiment, the cardiovascular disease is atherosclerosis.

In another embodiment, the cardiovascular disease is congestive heartfailure.

In another embodiment, the cardiovascular disease is coronary arterydisease.

Combination Therapy

In one embodiment, the present invention provides methods for treating aCondition in a patient, the method comprising administering to thepatient one or more Pyrimidine Derivatives, or a pharmaceuticallyacceptable salt, solvate, ester, prodrug or stereoisomer thereof and atleast one additional therapeutic agent that is not a PyrimidineDerivative, wherein the amounts administered are together effective totreat or prevent a Condition.

Non-limiting examples of additional therapeutic agents useful in thepresent methods for treating or preventing a Condition include,anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, cholesterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer protein (CETP) inhibitors, low-densitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stands, fatty acid esters of plant stands, or anycombination of two or more of these additional therapeutic agents.

Non-limiting examples of anti-obesity agents useful in the presentmethods for treating a Condition include CB1 antagonists or inverseagonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists,MCH receptor antagonists, histamine H₃ receptor antagonists or inverseagonists, metabolic rate enhancers, nutrient absorption inhibitors,leptin, appetite suppressants and lipase inhibitors.

Non-limiting examples of appetite suppressant agents useful in thepresent methods for treating or preventing a Condition includecannabinoid receptor 1 (CB₁) antagonists or inverse agonists (e.g.,rimonabant); Neuropeptide Y (NPY1, NPY2, NPY4 and NPY5) antagonists;metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g.,2-methyl-6-(phenylethynyl)-pyridine and3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine); melanin-concentratinghormone receptor (MCH1R and MCH2R) antagonists; melanocortin receptoragonists (e.g., Melanotan-II and Mc4r agonists); serotonin uptakeinhibitors (e.g., dexfenfluramine and fluoxetine); serotonin (5HT)transport inhibitors (e.g., paroxetine, fluoxetine, fenfluramine,fluvoxamine, sertaline and imipramine); norepinephrine (NE) transporterinhibitors (e.g., desipramine, talsupram and nomifensine); ghrelinantagonists; leptin or derivatives thereof; opioid antagonists (e.g.,nalmefene, 3-methoxynaltrexone, naloxone and nalterxone); orexinantagonists; bombesin receptor subtype 3 (BRS3) agonists;Cholecystokinin-A (CCK-A) agonists; ciliary neurotrophic factor (CNTF)or derivatives thereof (e.g., butabindide and axokine); monoaminereuptake inhibitors (e.g., sibutramine); glucagon-like peptide 1 (GLP-1)agonists; topiramate; and phytopharm compound 57.

Non-limiting examples of metabolic rate enhancers useful in the presentmethods for treating or preventing a Condition include acetyl-CoAcarboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 (33)agonists; diacylglycerol acyltransferase inhibitors (DGAT1 and DGAT2);fatty acid synthase (FAS) inhibitors (e.g., Cerulenin);phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline,zaprinast, sildenafil, aminone, milrinone, cilostamide, rolipram andcilomilast); thyroid hormone β agonists; uncoupling protein activators(UCP-1, 2 or 3) (e.g., phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acidand retinoic acid); acyl-estrogens (e.g., oleoyl-estrone);glucocorticoid antagonists; 11-beta hydroxy steroid dehydrogenase type 1(11β HSD-1) inhibitors; melanocortin-3 receptor (Mc3r) agonists; andstearoyl-CoA desaturase-1 (SCD-1) compounds.

Non-limiting examples of nutrient absorption inhibitors useful in thepresent methods for treating or preventing a Condition include lipaseinhibitors (e.g., orlistat, lipstatin, tetrahydrolipstatin, teasaponinand diethylumbelliferyl phosphate); fatty acid transporter inhibitors;dicarboxylate transporter inhibitors; glucose transporter inhibitors;and phosphate transporter inhibitors.

Non-limiting examples of cholesterol biosynthesis inhibitors useful inthe present methods for treating or preventing a Condition includeHMG-CoA reductase inhibitors, squalene synthase inhibitors, squaleneepoxidase inhibitors, and mixtures thereof.

Non-limiting examples of cholesterol absorption inhibitors useful in thepresent methods for treating or preventing a Condition includeezetimibe. In one embodiment, the cholesterol absorption inhibitor isezetimibe.

HMG-CoA reductase inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, statins suchas lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin,cerivastatin, CI-981, resuvastatin, rivastatin, pitavastatin,rosuvastatin or L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid).

Squalene synthesis inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, squalenesynthetase inhibitors; squalestatin 1; and squalene epoxidaseinhibitors, such as NB-5.98((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride).

Bile acid sequestrants useful in the present methods for treating orpreventing a Condition include, but are not limited to, cholestyramine(a styrene-divinylbenzene copolymer containing quaternary ammoniumcationic groups capable of binding bile acids, such as QUESTRAN® orQUESTRAN LIGHT® cholestyramine which are available from Bristol-MyersSquibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Suitableinorganic cholesterol sequestrants include bismuth salicylate plusmontmorillonite clay, aluminum hydroxide and calcium carbonate antacids.Probucol derivatives useful in the present methods for treating orpreventing a Condition include, but are not limited to, AGI-1067 andothers disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250.

IBAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, benzothiepines such astherapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine1,1-dioxide structure such as are disclosed in International PublicationNo. WO 00/38727. Nicotinic acid receptor agonists useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, those having a pyridine-3-carboxylate structure or apyrazine-2-carboxylate structure, including acid forms, salts, esters,zwitterions and tautomers, where available. Other examples of nicotinicacid receptor agonists useful in the present methods include nicotinicacid, niceritrol, nicofuranose and acipimox. An example of a suitablenicotinic acid product is NIASPAN® (niacin extended-release tablets)which are available from Kos Pharmaceuticals, Inc. (Cranbury, N.J.).Further nicotinic acid receptor agonists useful in the present methodsfor treating or preventing a Condition include, but are not limited to,the compounds disclosed in U.S. Patent Publication Nos. 2006/0264489 and2007/0066630, and U.S. patent application Ser. No. 11/771,538, each ofwhich is incorporated herein by reference.

ACAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, avasimibe, HL-004,lecimibide and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]-methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July; 60(1); 55-93, whichis incorporated by reference herein.

CETP inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, those disclosed inInternational Publication No. WO 00/38721 and U.S. Pat. No. 6,147,090,each of which are incorporated herein by reference.

LDL-receptor activators useful in the present methods for treating orpreventing a Condition include, but are not limited to, include HOE-402,an imidazolidinyl-pyrimidine derivative that directly stimulates LDLreceptor activity. See M. Huettinger et al., “Hypolipidemic activity ofHOE-402 is Mediated by Stimulation of the LDL Receptor Pathway”,Arterioscler. Thromb. 1993; 13:1005-12.

Natural water-soluble fibers useful in the present methods for treatingor preventing a Condition include, but are not limited to, psyllium,guar, oat and pectin.

Fatty acid esters of plant stanols useful in the present methods fortreating or preventing a Condition include, but are not limited to, thesitostanol ester used in BENECOL® margarine.

Non-limiting examples of antidiabetic agents useful in the presentmethods for treating a Condition include insulin sensitizers,α-glucosidase inhibitors, DPP-IV inhibitors, insulin secretagogues,hepatic glucose output lowering compounds, antihypertensive agents,sodium glucose uptake transporter 2 (SGLT-2) inhibitors, insulin andinsulin-containing compositions, and anti-obesity agents as set forthabove.

In one embodiment, the antidiabetic agent is an insulin secretagogue. Inone embodiment, the insulin secretagogue is a sulfonylurea.

Non-limiting examples of sulfonylureas useful in the present methodsinclude glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide,acetohexamide, gliamilide, gliclazide, gliquidone, glibenclamide andtolazamide.

In another embodiment, the insulin secretagogue is a meglitinide.

Non-limiting examples of meglitinides useful in the present methods fortreating a Condition include repaglinide, mitiglinide, and nateglinide.

In still another embodiment, the insulin secretagogue is GLP-1 or aGLP-1 mimetic.

Non-limiting examples of GLP-1 mimetics useful in the present methodsinclude Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem,Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (ZealandPharmaceuticals), and compounds disclosed in International PublicationNo. WO 00/07617.

Other non-limiting examples of insulin secretagogues useful in thepresent methods include exendin, GIP and secretin.

In another embodiment, the antidiabetic agent is an insulin sensitizer.

Non-limiting examples of insulin sensitizers useful in the presentmethods include PPAR activators or agonists, such as troglitazone,rosiglitazone, pioglitazone and englitazone; biguanidines such asmetformin and phenformin; PTP-1B inhibitors; and glucokinase activators.

In another embodiment, the antidiabetic agent is a α-Glucosidaseinhibitor.

Non-limiting examples of α-Glucosidase inhibitors useful the presentmethods include miglitol, acarbose, and voglibose.

In another embodiment, the antidiabetic agent is an hepatic glucoseoutput lowering agent.

Non-limiting examples of hepatic glucose output lowering agents usefulin the present methods include Glucophage and Glucophage XR.

In yet another embodiment, the antidiabetic agent is insulin, includingall formulations of insulin, such as long acting and short acting formsof insulin. Non-limiting examples of orally administrable insulin andinsulin containing compositions include AL-401 from Autoimmune, and thecompositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405;4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632;6,191,105; and International Publication No. WO 85/05029, each of whichis incorporated herein by reference.

In another embodiment, the antidiabetic agent is a DPP-IV inhibitor.

Non-limiting examples of DPP-IV inhibitors useful in the present methodsinclude sitagliptin, saxagliptin (Januvia™ Merck), denagliptin,vildagliptin (Galvus™, Novartis), alogliptin, alogliptin benzoate,ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph),BI-A and BI-α (Boehringer Ingelheim), SYR-322 (Takeda), MP-513(Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination ofsitagliptin/metformin HCl (Janumet™, Merck).

In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.

Non-limiting examples of SGLT-2 inhibitors useful in the present methodsinclude dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) andT-1095 (Tanabe Seiyaku).

Non-limiting examples of antihypertensive agents useful in the presentmethods for treating a Condition include β-blockers and calcium channelblockers (for example diltiazem, verapamil, nifedipine, amlopidine, andmybefradil), ACE inhibitors (for example captopril, lisinopril,enalapril, spirapril, ceranopril, zefenopril, fosinopril, cilazopril,and quinapril), AT-1 receptor antagonists (for example losartan,irbesartan, and valsartan), renin inhibitors and endothelin receptorantagonists (for example sitaxsentan).

In one embodiment, the antidiabetic agent is an agent that slows orblocks the breakdown of starches and certain sugars.

Non-limiting examples of antidiabetic agents that slow or block thebreakdown of starches and certain sugars and are suitable for use in thecompositions and methods of the present invention includealpha-glucosidase inhibitors and certain peptides for increasing insulinproduction. Alpha-glucosidase inhibitors help the body to lower bloodsugar by delaying the digestion of ingested carbohydrates, therebyresulting in a smaller rise in blood glucose concentration followingmeals. Non-limiting examples of suitable alpha-glucosidase inhibitorsinclude acarbose; miglitol; camiglibose; certain polyamines as disclosedin WO 01/47528 (incorporated herein by reference); voglibose.Non-limiting examples of suitable peptides for increasing insulinproduction including amlintide (CAS Reg. No. 122384-88-7 from Amylin;pramlintide, exendin, certain compounds having Glucagon-like peptide-1(GLP-1) agonistic activity as disclosed in International. PublicationNo. WO 00/07617.

Other specific additional therapeutic agents useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, rimonabant, 2-methyl-6-(phenylethynyl)-pyridine,3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-II,dexfenfluramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine,sertaline, imipramine, desipramine, talsupram, nomifensine, leptin,nalmefene, 3-methoxynaltrexone, naloxone, nalterxone, butabindide,axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin,theophylline, pentoxifylline, zaprinast, sildenafil, aminone, milrinone,cilostamide, rolipram, cilomilast, phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid,retinoic acid, oleoyl-estrone, orlistat, lipstatin, tetrahydrolipstatin,teasaponin and diethylumbelliferyl phosphate.

In one embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Pyrimidine Derivative, anantidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Pyrimidine Derivative andan antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a Pyrimidine Derivative andan anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Pyrimidine Derivative, anantidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Pyrimidine Derivative and anantidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a Pyrimidine Derivative and ananti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a PyrimidineDerivative and one or more additional therapeutic agents selected from:anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, sterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer protein (CETP) inhibitors, low-densitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stanols and fatty acid esters of plant stanols.

In one embodiment, the additional therapeutic agent is a cholesterolbiosynthesis inhibitor. In another embodiment, the cholesterolbiosynthesis inhibitor is a squalene synthetase inhibitor. In anotherembodiment, the cholesterol biosynthesis inhibitor is a squaleneepoxidase inhibitor. In still another embodiment, the cholesterolbiosynthesis inhibitor is an HMG-CoA reductase inhibitor. In anotherembodiment, the HMG-CoA reductase inhibitor is a statin. In yet anotherembodiment, the statin is lovastatin, pravastatin, simvastatin oratorvastatin.

In one embodiment, the additional therapeutic agent is a cholesterolabsorption inhibitor. In another embodiment, the cholesterol absorptioninhibitor is ezetimibe.

In one embodiment, the additional therapeutic agent comprises acholesterol absorption inhibitor and a cholesterol biosynthesisinhibitor. In another embodiment, the additional therapeutic agentcomprises a cholesterol absorption inhibitor and a statin. In anotherembodiment, the additional therapeutic agent comprises ezetimibe and astatin. In another embodiment, the additional therapeutic agentcomprises ezetimibe and simvastatin.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a PyrimidineDerivative, an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a PyrimidineDerivative and an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a PyrimidineDerivative and an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing a cardiovascular disease comprise administering one or morePyrimidine Derivatives, and an additional agent useful for treating orpreventing a cardiovascular disease.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts).

In one embodiment, the one or more Pyrimidine Derivatives areadministered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more Pyrimidine Derivatives and theadditional therapeutic agent(s) are administered in doses commonlyemployed when such agents are used as monotherapy for treating aCondition.

In another embodiment, the one or more Pyrimidine Derivatives and theadditional therapeutic agent(s) are administered in doses lower than thedoses commonly employed when such agents are used as monotherapy fortreating a Condition.

In still another embodiment, the one or more Pyrimidine Derivatives andthe additional therapeutic agent(s) act synergistically and areadministered in doses lower than the doses commonly employed when suchagents are used as monotherapy for treating a Condition.

In one embodiment, the one or more Pyrimidine Derivatives and theadditional therapeutic agent(s) are present in the same composition. Inone embodiment, this composition is suitable for oral administration. Inanother embodiment, this composition is suitable for intravenousadministration.

The one or more Pyrimidine Derivatives and the additional therapeuticagent(s) can act additively or synergistically. A synergisticcombination may allow the use of lower dosages of one or more agentsand/or less frequent administration of one or more agents of acombination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of one or more PyrimidineDerivatives and the additional therapeutic agent(s) may inhibit theresistance of a Condition to these agents.

In one embodiment, when the patient is treated for diabetes or adiabetic complication, the additional therapeutic agent is anantidiabetic agent which is not a Pyrimidine Derivative. In anotherembodiment, the additional therapeutic agent is an agent useful forreducing any potential side effect of a Pyrimidine Derivative. Suchpotential side effects include, but are not limited to, nausea,vomiting, headache, fever, lethargy, muscle aches, diarrhea, generalpain, and pain at an injection site.

In one embodiment, the additional therapeutic agent is used at its knowntherapeutically effective dose. In another embodiment, the additionaltherapeutic agent is used at its normally prescribed dosage. In anotherembodiment, the additional therapeutic agent is used at less than itsnormally prescribed dosage or its known therapeutically effective dose.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention of aCondition can be determined by the attending clinician, taking intoconsideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the patient; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Pyrimidine Derivative(s) and the otheragent(s) for treating diseases or conditions listed above can beadministered simultaneously or sequentially. This particularly usefulwhen the components of the combination are given on different dosingschedules, e.g., one component is administered once daily and anotherevery six hours, or when the preferred pharmaceutical compositions aredifferent, e.g. one is a tablet and one is a capsule. A kit comprisingthe separate dosage forms is therefore advantageous. Generally, a totaldaily dosage of the one or more Pyrimidine Derivatives and theadditional therapeutic agent(s) can when administered as combinationtherapy, range from about 0.1 to about 2000 mg per day, althoughvariations will necessarily occur depending on the target of thetherapy, the patient and the route of administration. In one embodiment,the dosage is from about 0.2 to about 100 mg/day, administered in asingle dose or in 2-4 divided doses. In another embodiment, the dosageis from about 1 to about 500 mg/day, administered in a single dose or in2-4 divided doses. In another embodiment, the dosage is from about 1 toabout 200 mg/day, administered in a single dose or in 2-4 divided doses.In still another embodiment, the dosage is from about 1 to about 100mg/day, administered in a single dose or in 2-4 divided doses. In yetanother embodiment, the dosage is from about 1 to about 50 mg/day,administered in a single dose or in 2-4 divided doses. In a furtherembodiment, the dosage is from about 1 to about 20 mg/day, administeredin a single dose or in 2-4 divided doses.

Compositions and Administration

In one embodiment, the invention provides compositions comprising aneffective amount of one or more Pyrimidine Derivatives or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof, and a pharmaceutically acceptable carrier.

For preparing compositions comprising one or more PyrimidineDerivatives, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. The powdersand tablets may be comprised of from about 5 to about 95 percent activeingredient. Suitable solid carriers are known in the art, e.g. magnesiumcarbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders,cachets and capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition,(1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

In one embodiment, a Pyrimidine Derivative is administered orally.

In another embodiment, the pharmaceutical preparation is in a unitdosage form. In such form, the preparation is subdivided into suitablysized unit doses containing appropriate quantities of the activecomponent, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation is fromabout 0.1 to about 2000 mg. Variations will necessarily occur dependingon the target of the therapy, the patient and the route ofadministration. In one embodiment, the unit dose dosage is from about0.2 to about 1000 mg. In another embodiment, the unit dose dosage isfrom about 1 to about 500 mg. In another embodiment, the unit dosedosage is from about 1 to about 100 mg/day. In still another embodiment,the unit dose dosage is from about 1 to about 50 mg. In yet anotherembodiment, the unit dose dosage is from about 1 to about 10 mg.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, the condition and size of the patient,as well as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day toabout 300 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50mg/day, or 1 mg/day to about 20 mg/day, in one dose or in two to fourdivided doses.

When the invention comprises a combination of one or more PyrimidineDerivatives and an additional therapeutic agent, the two activecomponents may be co-administered simultaneously or sequentially, or asingle composition comprising one or more Pyrimidine Derivatives and theadditional therapeutic agent(s) in a pharmaceutically acceptable carriercan be administered. The components of the combination can beadministered individually or together in any conventional dosage formsuch as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the additional therapeuticagent can be determined from published material, and may range fromabout 1 to about 1000 mg per dose. In one embodiment, when used incombination, the dosage levels of the individual components are lowerthan the recommended individual dosages because of an advantageouseffect of the combination.

In one embodiment, the components of a combination therapy regimen areto be administered simultaneously, they can be administered in a singlecomposition with a pharmaceutically acceptable carrier.

In another embodiment, when the components of a combination therapyregimen are to be administered separately or sequentially, they can beadministered in separate compositions, each containing apharmaceutically acceptable carrier.

Kits

In one aspect, the present invention provides a kit comprising aneffective amount of one or more Pyrimidine Derivatives, or apharmaceutically acceptable salt or solvate of the compound and apharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of one or more Pyrimidine Derivatives, and an amount of one ormore additional therapeutic agents, wherein the combined amounts areeffective for enhancing the memory of a patient or effective fortreating or preventing a cognitive disorder in a patient.

When the components of a combination therapy regimen are to are to beadministered in more than one composition, they can be provided in a kitcomprising comprising: (a) one or more Pyrimidine Derivatives togetherin a pharmaceutically acceptable carrier in a single container, or (b)one or more Pyrimidine Derivatives in separate containers, each in apharmaceutically acceptable carrier, and (c) one or more additionaltherapeutic agents together in a pharmaceutically acceptable carrier ina single container or (d) one or more additional therapeutic agents inseparate containers, each in a pharmaceutically acceptable carrier; suchthat the active components of the combination therapy are present inamounts that render the combination therapeutically effective.

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures ofwhich are incorporated herein by reference.

1. A compound having the formula:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof, wherein: R¹ is H, alkyl, halo or —O-alkyl; R^(2a) is H oralkyl, or R^(2a) and R^(2b) join to form —CH₂CH₂—, —CH₂CH₂CH₂— or—CH₂OCH₂—; R^(2b) is H or alkyl; R^(3a) is H or alkyl, or R^(3a) andR^(3b) join to form —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂OCH₂—; R^(3b) is H oralkyl; R⁴ is alkyl, cycloalkyl, haloalkyl, aryl, -alkylene-aryl orheteroaryl, wherein an aryl or heteroaryl group can be optionallysubstituted with one or more groups, which can be the same or different,and are selected from alkyl, halo, haloalkyl, —O-alkyl, —CN and—S(O)₂-alkyl; R⁵ is alkyl, cycloalkyl, haloalkyl, -alkylene-aryl,alkenyl or —N(alkyl)₂; R⁶ is H or alkyl; A is a bond when Q is —N—, andA is —N(R⁶)— when Q is —CH—; Q is —N— or —CH—; W is —C(O)—, —C(O)O—, or—S(O)₂—; Y is —O—, —S—, —NH— or —CH₂— when Z is —CH—, and Y is a bondwhen Z is —N—; Z is —CH— or —N—; each occurrence of n is independently0, 1 or 2; and each occurrence of p is 0, 1 or 2, such that when Q and Zare both —N—, then each occurrence of p is 1 or
 2. 2-23. (canceled) 24.The compound of claim 1 having the formula:

wherein: R¹ is H, alkyl, —O-alkyl or halo; R⁴ is alkyl, cycloalkyl,haloalkyl, aryl, -alkylene-aryl or heteroaryl, wherein an aryl orheteroaryl group can be optionally substituted with one or more groups,which can be the same or different, and are selected from alkyl, halo,haloalkyl, —O-alkyl, —CN and —S(O)₂-alkyl; R⁵ is alkyl, cycloalkyl,haloalkyl, -alkylene-aryl, alkenyl or —N(alkyl)₂; W is —C(O)O—, —C(O)—or —S(O)₂—; and Y is —O—, —S—, —CH₂— or —NH—.
 25. The compound of claim24, wherein R¹ is methyl, methoxy or F. 26-37. (canceled)
 38. A compoundhaving the structure:

or a pharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof.
 39. A composition comprising an effective amountof one or more compounds of claim 1 or a pharmaceutically acceptablesalt, solvate, ester, prodrug or stereoisomer thereof, and at least onepharmaceutically acceptable carrier.
 40. A composition comprising aneffective amount of one or more compounds of claim 38 or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof, and at least one pharmaceutically acceptablecarrier.
 41. A method for treating diabetes, obesity or metabolicsyndrome in a patient, the method comprising administering to thepatient an effective amount of one or more compounds of claim 1 or apharmaceutically acceptable salt, solvate, ester, prodrug orstereoisomer thereof. 42-52. (canceled)
 53. The compound of claim 1,wherein Y is a bond, —CH₂, —NH—, —O— or —S—; W is —C(O)O—, —C(O)— or—S(O)₂—; and Z is —CH— or —N—.
 54. The compound of claim 1, wherein eachoccurrence of n is 1 and each occurrence of p is
 1. 55. The compound ofclaim 1, wherein R¹ is methyl, methoxy or F.
 56. The compound of claim1, wherein R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridylor phenyl, where a pyridyl or phenyl group can be optionally substitutedwith one or more groups, which can be the same or different, and whichare selected from halo and haloalkyl.
 57. The compound of claim 1,wherein R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl,—N(CH₃)₂ or allyl.
 58. The compound of claim 1, wherein W is —C(O)O—,—C(O)—, or —S(O)₂ and R⁴ is alkyl, aryl, heteroaryl, -alkylene-aryl,alkenyl, cycloalkyl or —N(alkyl)₂.
 59. The compound of claim 1, whereinR^(2a), R^(2b), R^(3a) and R^(3b) are each H, or combine to form—CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂OCH₂—.
 60. The compound of claim 24,wherein R¹ is methyl, methoxy or F.
 61. The compound of claim 24,wherein R⁴ is isopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridyl orphenyl, where a pyridyl or phenyl group can be optionally substitutedwith one or more groups, which can be the same or different, and whichare selected from halo and haloalkyl.
 62. The compound of claim 24,wherein R⁵ is methyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl,—N(CH₃)₂ or allyl.
 63. The compound of claim 24, wherein W is —C(O)O—,—C(O)—, or —S(O)₂ and R⁴ is alkyl, aryl, heteroaryl, -alkylene-aryl,alkenyl, cycloalkyl or —N(alkyl)₂ and Y is —O—.
 64. The compound ofclaim 24, wherein Y is —O—; R⁴ is isopropyl, allyl, cyclopropyl,t-butyl, ethyl, pyridyl or phenyl, where a pyridyl or phenyl group canbe optionally substituted with one or more groups, which can be the sameor different, and which are selected from halo and haloalkyl; and R⁵ ismethyl, isopropyl, cyclopropyl, ethyl, —CH₂CF₃, benzyl, —N(CH₃)₂ orallyl.